HBV reactivation in patients with rheumatoid arthritis treated with anti-interleukin-6: a systematic review and meta-analysis

Abstract Objective The objective of this study was to assess the possibility of HBV reactivation (HBVr) in patients with RA under anti-IL-6 treatment. Methods Using PubMed, Scopus and EMBASE, we performed a systematic literature search for articles related to HBVr in RA patients under anti-IL-6 treatment. The search was performed with no date limits and was last updated 28 January 2023. The results from all the databases were combined and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and paediatric studies. Results Our initial search led to 427 articles; 28 were duplicates, 46 non-English, 169 reviews, 31 books/letters, 25 case reports, and 88 irrelevant to the meta-analysis aim; 21 were excluded due to inadequate information, leaving 19 articles, with a sum of 372 RA patients with chronic HBV (CHB) or resolved HBV infection, for further analysis. The overall risk for HBVr in RA patients with CHB was 6.7%, increasing to 37% when only RA patients with CHB and no antiviral prophylaxis were included. On the contrary, HBVr was close to 0% in RA patients with resolved HBV infection, irrespective of antiviral prophylaxis. All RA patients experiencing HBVr in these studies were successfully managed with antiviral treatment and/or drug withdrawal. Conclusion Overall, anti-IL-6 treatment comes with a significant risk of HBVr in RA patients with CHB; risk is diminished when antiviral prophylaxis is used. In contrast, in RA patients with resolved HBV infection, the risk of HBVr seems to be extremely low. Large, well-designed studies (either controlled trials or multicentre/international observational studies) are warranted to further validate these results.


Introduction
Hepatitis B reactivation (HBVr) is a well-recognized problem in everyday practice in patients receiving immunosuppressive/ immunomodulatory treatment, like those living with autoimmune inflammatory rheumatic diseases (AIIRDs) [1].
The definition of HBVr differs among various guidelines; however, it can be summarized as a HBV DNA rise of >10-fold to 100-fold in patients with detectable HBV DNA at baseline, or as HBV DNA and/or HBsAg appearance in patients who are HBV DNA-or HBsAg-negative at baseline, respectively [2,3].The clinical course of HBVr varies from a simple HBV DNA rise and HBsAg seropositivity without hepatitis, to mild reactivation with clinical hepatitis, or even fulminant liver failure with transaminasaemia, encephalopathy Rheumatology key messages • HBV reactivation risk in RA patients with chronic hepatitis B was 37%.
• HBV reactivation risk in RA patients was almost 0% in patients with resolved HBV infection.
• No RA patients under antiviral prophylaxis suffered HBV reactivation.
For patients living with an AIIRD, HBVr risk seems higher in patients receiving B cell-depleting therapies like rituximab, even though this risk is probably lower when compared with that of patients with lymphoma [1,3,[10][11][12].The use of TNF inhibitors also poses a considerable risk, as does the prolonged use of CSs, especially in high doses [1,5,[13][14][15], while HBVr risk seems to be low in patients under conventional DMARDs [1,5].Data regarding HBVr in patients under treatment with anti-IL-6 (one of the major bDMARDs used in RA) are scarce [16,17].Notably, IL-6 is a cytokine that controls a number of pathways, promoting also liver regeneration and hence playing a crucial role potentially in protecting against HBV infection [18,19].
The aim of this systematic literature review and metaanalysis was to analyse the risk of HBVr in patients with RA under anti-IL-6 treatment.

Method
The meta-analysis was conducted following the recommended items of Systematic Reviews and Meta-Analysis (PRISMA) guidelines [20] and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [21].The Newcastle-Ottawa scale (score 0-9) was used to assess the quality of the non-randomized controlled trials (RCTs) [22].The quality of the studies was assessed by two investigators (S.K., T.A.), and in the case of disagreement consensus was reached upon discussion with a third assessor (G.E.F.).This article is based on previously conducted studies; the authors did not undertake any new studies involving human participants or animals.

Study identification
We performed a systematic literature search for relevant articles using PubMed, Scopus and EMBASE.The search was performed with no date limits and was last updated on 28 January 2023.The search strategy focused on the following search terms: 'tocilizumab' (All Fields) OR 'sarilumab' (All Fields) OR 'immunosuppression therapy' (MeSH Terms) OR 'immunosuppressive therapy'(All Fields) AND 'HBV' (All Fields) OR 'hepatitis b'(MeSH Terms) OR 'hepatitis b'(All Fields) AND 'arthritis, rheumatoid'(MeSH Terms) OR 'RA' (All Fields) OR 'autoimmune diseases' (MeSH Terms) OR 'autoimmune diseases' (All Fields) OR 'rheumatic diseases' (MeSH Terms) OR 'rheumatic diseases'(All Fields).Reference lists of relevant articles were also reviewed.
The search results were screened by two independent reviewers (S.K., T.A.) using the titles and abstracts, and all articles considered relevant were evaluated in full-text format.In the case of a disagreement, consensus was reached after discussion with a third reviewer (G.E.F.).The results from all databases were combined, and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and studies with paediatric populations.

Statistical analysis
A meta-analysis was performed using both the fixed and random effects methods.Since it was not feasible to collect detailed information for each individual patient, the analysis was performed on the aggregated data; such data were extracted from the reported results of the studies after determination of their significance.The meta-analysis was conducted using the R statistical computing language (edition 4.2.2) [23], within the Windows (Microsoft) environment and using the specialized package meta for the R language [24,25].In the studies in which the mean value and S.D. were not reported, the median and first and third quartiles were used to estimate the mean value and S.D., as proposed by Hozo et al. [26].An improved method suggested by Bland was also used in cases where the maximum and minimum values were reported [27].For such estimations of the mean value and S.D., the software Deep Meta Tool, Version 1 was used [28].If only the minimum and maximum values were reported, then the range rule was applied to estimate the S.D., and the mean value was considered equal to the median.Finally, for studies based on case series with detailed information for each patient, the mean value and S.D. were calculated.In studies reporting on multiple groups treated with different agents, these groups were included separately in the meta-analysis.Assessment for risk of bias at the individual study level was not performed; however, risk of bias was evaluated cumulatively by the relevant funnel plots.

Meta-analysis
Patients included in the meta-analysis A total of 372 patients with CHB or resolved HBV infection were included in the meta-analysis, with a median age of 64 years (range 18-91 years); data on gender were largely lacking; out of the 74 patients for whom gender was reported, 25 were male (33.8%).Forty-one patients had CHB and 279 had resolved HBV infection, with only 19 patients receiving antiviral prophylaxis upon anti-IL-6 initiation (Table 2).Fourteen patients experienced HBVr, with a median time between anti-IL-6 initiation and HBVr of 5.5 months (range 1-86 months).Of note, none of the patients experiencing HBVr were under antiviral treatment (Table 2).A total of 5 patients initiated antiviral treatment after HBVr, all with entecavir.No deaths after HBVr were reported.
HBV reactivation in patients with RA treated with anti-interleukin-6 HBVr rates based on HBV status In order to calculate HBVr risk based on a patient's HBV status, we divided our patients into two groups: group 1 included patients with CHB and group 2 included patients with resolved HBV infection.
For both groups, the forest plot (Fig. 2) showed acceptable heterogeneity (I 2 ¼ 51%) for patients for CHB and excellent heterogeneity (I 2 ¼ 0) for those with resolved HBV; the publication bias was minimal for both groups.The aggregated percentage of HBVr for patients with CHB was 6.7% (95% CI: 0-31.1%)(5.4% for the fixed effects model), and almost 0% for patients with resolved HBV (of the 718 patients in this group, 3 experienced HBVr; however, according to both the random and common effects models, the overall reactivation proportion was 0% (95% CI: 0-0.9%).The comparison of the aggregated reactivation percentages indicated that there was a statistically significant difference, with patients with CHB showing higher reactivation rates than patients with resolved HBV infection (P <0.04, for the fixed effects models).
HBVr in patients without antiviral prophylaxis Fig. 3 depicts the findings for the patients who did not receive antiviral prophylaxis.There was poor heterogeneity among patients with CHB (83%) and excellent homogeneity among patients with resolved HBV infection (0%); the publication bias was minimal.The aggregated percentage of the HBVr for patients with CHB was 31% (95% CI: 0-99%) (14.75% for the fixed effects model), while for patients with resolved HBV infection, the aggregated percentage of recurrence was almost 0% (of the 172 patients in this group, 3 experienced recurrence, resulting in a percentage recurrence of 1.7%, 95% CI: 0-3.7%); however, according to both the common and random effects models, the overall reactivation proportion for the meta-analysis approach was 0%, with the 95% CI: 0%.The comparison of the aggregated reactivation percentages indicated that there was a statistically significant difference, with patients with CHB showing higher reactivation rates than patients with resolved HBV infection (P < 0.01, for the common effects model).

Discussion
In this SLR and meta-analysis, we found that HBVr occurred in 7% of patients with CHB but was negligible in patients with resolved HBV infection.In the former group, HBVr risk rose up to 33% without anti-viral treatment administration.In contrast, HBVr remained trivial for RA individuals with resolved HBV infection who did not receive anti-viral treatment.
IL-6 is a pleiotropic cytokine exerting its action through a 130-kDa signal-transducing b-receptor (gp130), linked with either its membrane receptor (IL-6R) or its soluble receptor (sIL-6R) [48].Apart from being a main mediator of inflammatory processes, IL-6 is also involved in homeostatic liver mechanisms.In fact, it promotes liver regeneration and protects liver cells from injuries caused by immune responses, alcohol, and viral infections [49,50].Moreover, IL-6 seems to play a crucial role in protecting against HBV infection.First, it seems to exert a dose-dependent inhibition of HBV entry into hepatocytes by downregulating sodium taurocholate cotransporting polypeptide (NTCP), most likely by inhibiting hepatocyte nuclear factor-4-alpha (HNF4a) expression [51,52].Second, it also seems to inhibit covalently closed circular DNA (cccDNA) formation in HBV-infected cells and to control HBx expression and HBV replication [19,52].Finally, IL-6 may also prevent cccDNA accumulation, making its role a Patients with RA treated with anti-IL-6.b NS: Not specified.c The antiviral drug hasn't been specified.ADV: adefovir; ETV: entecavir; LMV: lamivudine; CHB: Chronic HBV infection; GCs: glucocorticoids.
crucial for host defence against HBV infection [50].Given the beneficial role of IL-6 in controlling HBV infection, the use of anti-IL-6 drugs could come with a certain risk of HBVr; however, data regarding this issue are scarce, limited mainly to case reports and small studies.As mentioned earlier, the HBV status (chronic vs resolved) of the patient is one of the most critical factors affecting the risk for HBVr.Thus, recent EULAR recommendations for the screening and prophylaxis of AIIRD patients for chronic and opportunistic infections suggest that all patients who are starting treatment with immunosuppressants/immunomodulators should be screened for HBV status, examining in the first instance HBsAg, anti-HBcore and anti-HBs [53].The same is also suggested by the recent EULAR recommendations for the use of IL-6 blockers in inflammatory conditions [54].It has been established that the risk for HBVr in individuals who have chronic HBV and are starting treatment with bDMARDs is considerably high, and referral to a hepatologist for administration of anti-viral treatment is imperative [53].A recent meta-analysis has shown that this also holds true for patients with inflammatory arthritis treated with TNF inhibitors [55].However, data for other bDMARDs are limited.In this SLR and meta-analysis, we demonstrate that this is the case for RA patients treated with tocilizumab as well.HBV reactivation in patients with RA treated with anti-interleukin-6 Regarding patients with resolved HBV infection, risk for HBVr appears to be much lower, and monitoring with liver function tests and HBV-DNA has been suggested over universal prophylaxis, in the recent EULAR recommendations [53].However, meta-analyses or large studies in these patients receiving anti-IL-6 drugs are lacking.Our data offer additional evidence that prophylaxis does not seem to be necessary for these patients, since HBVr seems to be a rather rare event, with a rate close to 0%.Even though these drugs are relatively safe and given once daily, anti-viral prophylaxis in these patients is most probably not cost-effective; instead, close monitoring with HBV-DNA and/or liver function tests would be a reasonable approach [56].Although the data are still limited, this seems to be the case for other biologic/targeted synthetic-DMARDs used for inflammatory arthritis, with the exception of rituximab, for which the risk for reactivation appears to be considerably higher [12,55,57,58].
Our study has important strengths, as well as limitations.To the best of our knowledge, we present the first metaanalysis of HBVr in patients with RA under anti-IL-6 treatment.On the other hand, the number of studies included in our meta-analysis is not high.However, the heterogeneity of these studies is found to be high enough in our analysis, and the results seem to be adequate, in our opinion, to draw some initial conclusions.Additionally, our meta-analysis is based on observational studies only, as there are no randomized controlled trials examining this issue.Of note, all studies included, were of acceptable quality, as assessed by the Newcastle-Ottawa scale.The latter, although having its drawbacks, has been widely used by EULAR and other In conclusion, our SLR and meta-analysis provide evidence that, in RA, for patients with CHB treated with anti-IL-6 drugs, prophylaxis and referral to a hepatologist should be made.On the other hand, for patients with resolved hepatitis, anti-viral prophylaxis does not seem to confer additional benefit, and close monitoring is most probably a more beneficial approach.More evidence is needed to reach robust conclusions, not just for IL-6 inhibitors but also for drug categories such as the JAK-inhibitors, to enable more informed and targeted clinical decisions.Towards this end, randomized controlled trials enrolling RA patients treated with a specific class of bDMARDs who have chronic or resolved hepatitis, receiving or not receiving anti-viral prophylaxis, would be desirable.Other types of studies could also be helpful.For example, relevant data derived from big registries or multicentre (and preferably international) observational studies designed for this purpose (i.e.HBVr after exposure to specific bDMARDs) would give some answers.T.A.All authors have read and agreed to the published version of the manuscript.

Figure 1 .
Figure 1.Flowchart for selection of articles.n: number

Figure 2 .
Figure 2. HBV reactivation rates in patients with CHB (group 1) and resolved HBV infection (group 2) and relevant funnel plot.The 'Events' column indicates the number of reactivation events; the 'Total' column indicates the total number of patients; the proportion corresponds to the relative proportion of reactivation events in the total population.CHB: chronic HBV

Table 1 .
Studies included in the meta-analysis